Levofloxacine, which is a common name of (S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyr ido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid hemihydrate in accordance with JAN (Japanese Accepted Name), is a compound demonstrating high antimicrobial effect and high safety (refer to JP-A-62-252790 or EP-A-0 206 283). The terms "JP-A" and "EP-A" as used herein mean an "unexamined published Japanese patent application" and "European patent publication", respectively. Thus, it is expected as an excellent synthetic antimicrobial agent.
In addition to levofloxacine which is a hemihydrate, crystals of (S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyr ido[1,2,3de][1,4]benzoxazine-6-carboxylic acid may be present in the form of a monohydrate differing in the number of water molecules in the crystal, or as anhydrous crystals obtained by dehydrating these hemi- and monohydrates.
A process is known for the production of levofloxacine which involves recrystallization or crystallization of levofloxacine from a solvent mixture of ethanol and diethyl ether or concentrated aqueous ammonia and ethanol (refer to JP-A-62-252790 or EP-A-0 206 283 as cited above). However, the use of the latter solvent mixture may cause the crystallization of (S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyr ido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid monohydrate, which will simply be called "monohydrate" hereinafter, together with the target levofloxacine (the hemihydrate form). The conversion of this monohydrate into the hemihydrate may be difficult to achieve in practice. Namely, when crystal water is removed from the monohydrate and the anhydrous crystals thus obtained are allowed to take up moisture, only the original monohydrate is obtained. When levofloxacine is contaminated with the monohydrate, therefore, the recrystallization or crystallization must be conducted till such contamination disappears.
Furthermore, anhydrous crystals obtained by removing crystal water cause blocking or sticking, and the industrial operations with them become troublesome. Accordingly, a method of preparing a hydrated crystal by the hydration of the dehydrated crystal is unsuitable as an industrial process.